Process for poducing beta-oxonitrile compound or alkali metal salt thereof

ABSTRACT

The present invention relates to a process for preparing a β-oxonitrile compound or an alkali metal salt thereof which comprises reacting a carboxylic ester represented by the formula (1):  
     R 1 CO 2 R 2   (1)  
     wherein R 1  and R 2  each represent a group which does not participate in a reaction, provided that R 2  excludes a hydrogen atom,  
     with a nitrile compound represented by the formula (2):  
     R 3 CH 2 CN  (2)  
     wherein R 3  represents an alkyl group,  
     and a base at 145 to 300° C. in a sealed vessel to obtain an alkali metal salt of a P-oxonitrile compound represented by the formula (3):  
                 
 
     wherein R 1  and R 3  have the same meanings as defined above,  
     and neutralizing the same with an acid, if necessary.

TECHNICAL FIELD

[0001] The present invention relates to a process for preparing aβ-oxonitrile compound or an alkali metal salt thereof useful forsynthetic starting materials for medicine, agricultural chemicals, etc.

BACKGROUND ART

[0002] As a method for producing a β-oxonitrile derivative or an alkalimetal salt thereof by reacting a nitrile compound with a carboxylicester, there has been disclosed a method, for example, in Romania PatentNo. 71248 (RO 71248), in which butyl acetate and propionitrile arereacted in the presence of sodium butoxide in xylene at 125 to 128° C.to obtain an alkali metal salt of α-acetylpropionitrile with a purity of85 to 87% and a yield of 70 to 75%, and neutralizing and purifying theproduct to obtain α-acetylpropionitrile with a yield of 50%. Also, inChemische Berichte (Chem. Ber.), 115, 355 (1982), there is disclosed amethod for obtaining 2-methyl-3-oxobutane nitrile by reacting ethylacetate and propionitrile in the presence of sodium hydride in benzenewith a yield of 34%, and further in Journal of American Chemical Society(J. Am. Chem. Soc.), 79, 723 (1957), there is disclosed a method forobtaining 2-methyl-3-oxobutane nitrile by reacting methyl acetate andpropionitrile in the presence of sodium amide in liquid ammonia with ayield of 63%.

[0003] However, in either of the methods, their yields are low and theyare not a method satisfied as an industrial preparation process.

[0004] An object of the present invention is to solve theabove-mentioned problems and to provide a process for preparing aβ-oxonitrile compound or an alkali metal salt thereof which is capableof obtaining a β-oxonitrile compound or an alkali metal salt thereofwith a high yield and suitable for industrial preparation process.

SUMMARY OF THE INVENTION

[0005] The problems to be solved by the present invention can be solvedby a process for preparing an alkali metal salt of a β-oxonitrilecompound which comprises reacting a carboxylic ester represented by theformula (1):

R¹CO₂R²  (1)

[0006] wherein R¹ and R² each represent a group which does notparticipate in a reaction, provided that R² excludes a hydrogen atom,

[0007] with a nitrile compound represented by the formula (2):

R³CH₂CN  (2)

[0008] wherein R³ represents an alkyl group,

[0009] and a base at 145 to 300° C. in a sealed vessel to obtain analkali metal salt of a β-oxonitrile compound represented by the formula(3):

[0010] wherein R¹ and R³ have the same meanings as defined above.

BEST MODE FOR CARRYING OUT THE INVENTION

[0011] The carboxylic ester to be used in the reaction of the presentinvention is a compound represented by the above-mentioned formula (1).In the formula (1), R¹ is a group which does not participate in thereaction, preferably a hydrogen atom, an alkyl group or an aryl groupwhich may have a substituent(s), and there may be specificallymentioned, for example, a hydrogen atom; a lower alkyl group having 1 to4 carbon atoms such as a methyl group, an ethyl group, a propyl group, abutyl group, etc.; and an aryl group having 6 to 14 carbon atoms such asa phenyl group, a naphthyl group, an anthryl group, etc. Incidentally,these groups contain various kinds of isomers.

[0012] As a substituent(s) for the above-mentioned alkyl group or arylgroup, there may be mentioned a lower alkoxy group having 1 to 4 carbonatoms such as a methoxy group, an ethoxy group, a propoxy group, abutoxy group, etc.; and a halogen atom such as a fluorine atom, achlorine atom, a bromine atom, an iodine atom, etc. Incidentally, anumber of the substituent(s) or a position thereof is not specificallylimited.

[0013] Also, in the formula (1), R² is a group which does notparticipate in the reaction except for a hydrogen atom, preferably analkyl group or an aryl group which may have a substituent(s),specifically, for example, a lower alkyl group having 1 to 4 carbonatoms such as a methyl group, an ethyl group, a propyl group, a butylgroup, etc.; and an aryl group having 6 to 14 carbon atoms such as aphenyl group, a naphthyl group, an anthryl group, etc. Incidentally,these groups contain various kinds of isomers.

[0014] As a substituent(s) for the above-mentioned alkyl group or arylgroup, there may be mentioned a lower alkoxy group having 1 to 4 carbonatoms such as a methoxy group, an ethoxy group, a propoxy group, abutoxy group, etc.; and a halogen atom such as a fluorine atom, achlorine atom, a bromine atom, an iodine atom, etc. Incidentally, anumber of the substituent(s) or a position thereof is not specificallylimited.

[0015] Specific examples of the carboxylic ester represented by theabove-mentioned formula (1), there may be mentioned, for example,formate, acetate, propionate, butyrate, etc.

[0016] The nitrile compound to be used in the reaction of the presentinvention is a compound represented by the above-mentioned formula (2).In the formula (2), R³ is an alkyl group, preferably an alkyl grouphaving 1 to 10 carbon atoms, and there may be specifically mentioned,for example, a methyl group, an ethyl group, a propyl group, a butylgroup, a pentyl group, a hexyl group, a heptyl group, an octyl group, anonyl group, a decyl group, etc. Incidentally, these groups containvarious kinds of isomers.

[0017] As a specific example of the nitrile compound represented by theabove-mentioned formula (2), there may be mentioned, for example,propionitrile, butyronitrile, valeronitrile, hexanenitrile,heptanenitrile, octanenitrile, nonanenitrile, decanenitrile,undecanenitrile, dodecanenitrile (respective compounds includerespective isomers).

[0018] An amount of the above-mentioned nitrile compound to be used ispreferably 0.05 to 20 mol, more preferably 0.1 to 10 mol based on 1 molof the carboxylic ester.

[0019] As the base to be used in the reaction of the present invention,there may be mentioned, for example, an alkali metal alkoxide such aslithium methoxide, sodium methoxide, potassium methoxide, lithiumethoxide, sodium ethoxide, potassium ethoxide, lithium n-butoxide,sodium n-butoxide, potassium n-butoxide, etc.; and a metal hydride suchas lithium hydride, sodium hydride, potassium hydride, etc., preferablysodium methoxide, sodium hydride, particularly preferably sodiummethoxide is used. Incidentally, these bases may be used singly or incombination of two or more kinds in admixture.

[0020] An amount of the above-mentioned base to be used is preferably0.05 to 10 mol, more preferably 0.1 to 5 mol based on 1 mol of thecarboxylic ester.

[0021] The reaction of the present invention is carried out in a closedreaction vessel, and a specific example of the reaction vessel to beused may be mentioned, for example, autoclave, etc.

[0022] The reaction of the present invention is carried out in thepresence or absence of a solvent. The solvent to be used is notspecifically limited so long as it does not participate in the reaction,and there may be mentioned, for example, a cyclic aliphatic hydrocarbonsuch as cyclohexane, cycloheptane, cyclooctane, etc.; a halogenatedaliphatic hydrocarbon such as 1,2-dichloroethane, etc.; an aromatichydrocarbon such as toluene, xylene, cumene, etc.; a halogenatedaromatic hydrocarbon such as chlorobenzene, bromobenzene, etc.; anitrated aromatic hydrocarbon such as nitrobenzene, etc.; an alcoholsuch as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butylalcohol, isobutyl alcohol, t-butyl alcohol, etc., preferably a cyclicaliphatic hydrocarbon or an aromatic hydrocarbon is used. Incidentally,these solvents may be used singly or in combination of two or more kindsin admixture.

[0023] An amount of the above-mentioned solvent may be optionallycontrolled depending on uniformity of the solution or stirability of thesame, and it is preferably 0 to 100 ml, more preferably 0 to 20 ml basedon 1 g of the carboxylic ester.

[0024] The reaction of the present invention is carried out by a methodin which, for example, in an atmosphere of an inert gas such asnitrogen, argon, etc., a carboxylic ester, a nitrile compound, a baseand a solvent are mixed, and the mixture is stirred at 145 to 300° C. ina closed vessel under a spontaneous pressure or a self pressure and thelike.

[0025] Incidentally, the spontaneous pressure or self pressure in thepresent invention means a pressure which occurs during the reaction byvaporizing a reaction mixture or a part thereof in a closed reactionvessel, and it is a pressure higher than normal pressure, preferably0.12 to 10 MPa.

[0026] The reaction temperature of the present invention may varydepending on the reaction pressure, and preferably 150 to 200° C.

[0027] An alkali metal salt of a β-oxonitrile compound can be obtainedby the reaction of the present invention, and it can be obtained bycarrying out, for example, concentration, filtration, etc., aftercompletion of the reaction. Also, the alkali metal salt is neutralizedin an aqueous solution by adding an inorganic acid such as hydrochloricacid, nitric acid, sulfuric acid, etc., or an organic acid such asacetic acid, benzoic acid, etc., whereby it can be obtained as a freeβ-oxonitrile compound. Also, these products may be further purified by aconventional method such as recrystallization, distillation, columnchromatography, etc.

EXAMPLES

[0028] Next, the present invention is specifically mentioned byreferring to Examples, but the scope of the present invention is notlimited by these.

Example 1 Synthesis of sodium salt of 3-cyano-2-butanone

[0029] In an autoclave made of glass having an inner volume of 300 mland equipped with a stirring device, a thermometer and a pressure gaugewere charged 30.2 g (0.26 mol) of n-butyl acetate, 33.1 g (0.60 mol) ofpropionitrile, 10.8 g (0.20 mol) of sodium methoxide and 83 ml ofxylene, and the mixture was reacted at 150° C. under spontaneouspressure (0.29 to 0.32 MPa (gauge pressure)) in a closed reaction vesselfor 2 hours under argon atmosphere. After completion of the reaction,the mixture was cooled to room temperature, and precipitated productswere collected by filtration and dried to give 20.9 g of a sodium saltof 3-cyano-2-butanone as colorless powder (isolation yield: 87.7%).

[0030] Physical property of sodium salt of 3-cyano-2-butanone was asfollows.

[0031]¹H-NMR (DMSO-d₆, δ (ppm)); 1.45 (3H, s), 1.75 (3H, s)

Comparative Example 1 Synthesis of sodium salt of 3-cyano-2-butanone

[0032] In a flask made of glass having an inner volume of 300 ml andequipped with a stirring device, a thermometer and a reflux condenserwere charged 30.2 g (0.26 mol) of n-butyl acetate, 33.1 g (0.60 mol) ofpropionitrile, 10.8 g (0.20 mol) of sodium methoxide and 83 ml ofxylene, and the mixture was reacted under reflux condition (90 to 94°C.) under normal pressure for 24 hours under nitrogen atmosphere. Aftercompletion of the reaction, the mixture was cooled to room temperature,and precipitated products were collected by filtration and dried to give10.1 g of a sodium salt of 3-cyano-2-butanone as colorless powder(isolation yield: 42.4%).

Example 2 Synthesis of 3-cyano-2-butanone

[0033] In a flask made of glass having an inner volume of 300 ml werecharged 30.0 g (0.25 mol) of sodium salt of 3-cyano-2-butanonesynthesized in the same manner as in Example 1, 40 ml of water and 100ml of ethyl acetate. Then, 21.7 ml (0.26 mol) of conc. hydrochloric acidwas gradually added and the organic layer was taken out and dried overanhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure to give 23.3 g of 3-cyano-2-butanone(isolation yield: 96.0%).

[0034] Physical property of 3-cyano-2-butanone was as follows.

[0035]¹H-NMR (DMSO-d₆, 6 (ppm)); 1.50 (3H, s), 2.38 (3H, s), 3.60 (1H,q)

Example 3 Synthesis of sodium salt of 3-cyano-2-butanone

[0036] The reaction was carried out in the same manner as in Example 1except for changing the reaction temperature in Example 1 to 170° C. Asa result, 21.9 g of a sodium salt of 3-cyano-2-butanone (isolationyield: 92.0%) was obtained as colorless powder.

Example 4 Synthesis of sodium salt of 3-cyano-2-butanone

[0037] The reaction was carried out in the same manner as in Example 1except for changing the reaction temperature in Example 1 to 200° C. Asa result, 20.3 g of a sodium salt of 3-cyano-2-butanone (isolationyield: 85.2%) was obtained as colorless powder.

Example 5 Synthesis of sodium salt of 3-cyano-2-butanone

[0038] The reaction was carried out in the same manner as in Example 3except for changing n-butyl acetate in Example 3 to 22.9 g (0.26 mol) ofethyl acetate. As a result, 21.3 g of a sodium salt of3-cyano-2-butanone (isolation yield: 89.4%) was obtained as colorlesspowder.

Example 6 Synthesis of sodium salt of 3-cyano-2-butanone

[0039] The reaction was carried out in the same manner as in Example 3except for changing a used amount of propionitrile in Example 3 to 44.1g (0.80 mol). As a result, 21.2 g of a sodium salt of 3-cyano-2-butanone(isolation yield: 89.0%) was obtained as colorless powder.

Example 7 Synthesis of sodium salt of 3-cyano-2-butanone

[0040] The reaction was carried out in the same manner as in Example 3except for not using xylene in Example 3. As a result, 18.9 g of asodium salt of 3-cyano-2-butanone (isolation yield: 79.3%) was obtainedas colorless powder.

Example 8 Synthesis of sodium salt of 2-benzoylpropionitrile

[0041] In an autoclave made of glass having an inner volume of 100 mland equipped with a stirring device, a thermometer and a pressure gaugewere charged 17.71 g (0.13 mol) of methyl benzoate, 8.27 g (0.15 mol) ofpropionitrile, 5.41 g (0.10 mol) of sodium methoxide and 40 ml oftoluene, and the mixture was reacted at 170° C. under spontaneouspressure (0.49 MPa (gauge pressure)) in a closed reaction vessel for 2hours under nitrogen atmosphere. After completion of the reaction, themixture was cooled to room temperature, and precipitated products werecollected by filtration and dried to give 15.80 g of sodium salt of2-benzoylpropionitrile as colorless powder (isolation yield: 87.2%).

[0042] Physical property of sodium salt of 2-benzoylpropionitrile was asfollows.

[0043]¹H-NMR (DMSO-d₆, 6 (ppm)); 1.64 (3H, s), 7.10 to 7.80 (5H, m)

Comparative Example 2 Synthesis of sodium salt of 2-benzoylpropionitrile

[0044] In a flask made of glass having an inner volume of 100 ml andequipped with a stirring device, a thermometer and a reflux condenserwere charged 17.71 g (0.13 mol) of methyl benzoate, 8.27 g (0.15 mol) ofpropionitrile, 5.41 g (0.10 mol) of sodium methoxide and 40 ml oftoluene, and the mixture was reacted under nitrogen atmosphere andreflux condition (90 to 94° C.) at normal pressure for 24 hours. Aftercompletion of the reaction, the mixture was cooled to room temperature,and precipitated products were collected by filtration and dried to give12.80 g of a sodium salt of 2-benzoylpropionitrile (isolation yield:70.6%) as colorless powder.

Example 9 Synthesis of sodium salt of 2-formylpropionitrile

[0045] In an autoclave made of glass having an inner volume of 100 mland equipped with a stirring device, a thermometer and a pressure gaugewere charged 9.63 g (0.13 mol) of ethyl formate, 8.27 g (0.15 mol) ofpropionitrile, 5.41 g (0.10 mol) of sodium methoxide and 40 ml oftoluene, and the mixture was reacted at 170° C. under spontaneouspressure (0.22 MPa (gauge pressure)) in a closed reaction vessel for 2hours under nitrogen atmosphere. After completion of the reaction, themixture was cooled to room temperature, and precipitated products werecollected by filtration and dried to give 7.35 g of a sodium salt of2-formylpropionitrile (isolation yield: 70.0%) as colorless powder.

[0046] Physical property of sodium salt of 2-formylpropionitrile was asfollows.

[0047]¹H-NMR (DMSO-d₆, 6 (ppm)); 1.42 (3H, s), 8.12 (1H, s)

Comparative Example 3 Synthesis of sodium salt of 2-formylpropionitrile

[0048] In a flask made of glass having an inner volume of 200 ml andequipped with a stirring device, a thermometer and a reflux condenserwere charged 9.63 g (0.13 mol) of ethyl formate, 8.27 g (0.15 mol) ofpropionitrile, 5.41 g (0.10 mol) of sodium methoxide and 40 ml oftoluene, and the mixture was reacted under nitrogen atmosphere at normalpressure at 90° C. for 24 hours. After completion of the reaction, themixture was cooled to room temperature, and precipitated products werecollected by filtration and dried to give 2.90 g of colorless powder.This powder was analyzed by ¹H-NMR (DMSO-d₆), and no sodium salt of2-formylpropionitrile was formed.

Example 10 Synthesis of sodium salt of 3-cyano-2-pentanone

[0049] In an autoclave made of glass having an inner volume of 300 mland equipped with a stirring device, a thermometer and a pressure gaugewere charged 30.2 g (0.26 mol) of n-butyl acetate, 41.7 g-(0.60 mol) ofbutyronitrile, 10.8 g (0.20 mol) of sodium methoxide and 83 ml ofxylene, and the mixture was reacted at 150° C. under spontaneouspressure (0.29 MPa (gauge pressure)) in a closed reaction vessel for 2hours under nitrogen atmosphere. After completion of the reaction, themixture was cooled to room temperature, and precipitated products werecollected by filtration and dried to give 23.4 g of a sodium salt of3-cyano-2-pentanone (isolation yield: 87.9%) as colorless powder.

[0050] Physical property of sodium salt of 3-cyano-2-pentanone was asfollows.

[0051]¹H-NMR (DMSO-d₆, 6 (ppm)); 0.83 (3H, t), 1.73 (3H, s), 1.92 (2H,q)

Example 11 Synthesis of 3-cyano-2-pentanone

[0052] In a flask made of glass having an inner volume of 300 ml werecharged 33.3 g (0.25 mol) of a sodium salt of 3-cyano-2-pentanonesynthesized in the same manner as in Example 10, 40 ml of water and 100ml of ethyl acetate. Then, 21.7 ml (0.26 mol) of conc. hydrochloric acidwas gradually added to the mixture, and the organic layer was taken outand dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure to give 26.4 g of3-cyano-2-pentanone (isolation yield: 95.0%) as colorless liquid.

[0053] Physical property of 3-cyano-2-pentanone was as follows.

[0054]¹H-NMR (DMSO-d₆, 6 (ppm)); 0.97 (3H, t), 1.95 to 2.22 (2H, m),2.26 (3H, s), 4.02 to 4.12 (1H, m)

UTILIZABILITY IN INDUSTRY

[0055] According to the present invention, a β-oxonitrile compound or analkali metal salt thereof can be obtained with a high yield, and aprocess for preparing a β-oxonitrile compound or an alkali metal saltthereof which is industrially suitable can be provided.

1. A process for preparing an alkali metal salt of a β-oxonitrilecompound which comprises reacting a carboxylic ester represented by theformula (1): R¹CO₂R²  (1) wherein R¹ and R² each represent a group whichdoes not participate in a reaction, provided that R² excludes a hydrogenatom, with a nitrile compound represented by the formula (2):R³CH₂CN  (2) wherein R³ represents an alkyl group, and a base at 145 to300° C. in a sealed vessel to obtain an alkali metal salt of aβ-oxonitrile compound represented by the formula (3):

wherein R¹ and R³ have the same meanings as defined above.
 2. Theprocess for preparing an alkali metal salt of a β-oxonitrile compoundaccording to claim 1, wherein a pressure at the time of the reaction is0.12 to 10 MPa.
 3. The process for preparing an alkali metal salt of aβ-oxonitrile compound according to claim 1 or 2, wherein the nitrilecompound is used in an amount of 0.05 to 20 mol based on 1 mol of thecarboxylic ester.
 4. The process for preparing an alkali metal salt of aβ-oxonitrile compound according to claim 1 or 2, wherein the nitrilecompound is used in an amount of 0.1 to 10 mol based on 1 mol of thecarboxylic ester.
 5. The process for preparing an alkali metal salt of aβ-oxonitrile compound according to any one of claims 1 to 4, wherein thebase is selected from the group consisting of an alkali metal alkoxideand a metal hydride.
 6. The process for preparing an alkali metal saltof a oxonitrile compound according to any one of claims 1 to 4, whereinthe base is selected from the group consisting of lithium methoxide,sodium methoxide, potassium methoxide, lithium ethoxide, sodiumethoxide, potassium ethoxide, lithium n-butoxide, sodium n-butoxide,potassium n-butoxide, lithium hydride, sodium hydride and potassiumhydride.
 7. The process for preparing an alkali metal salt of aβ-oxonitrile compound according to any one of claims 1 to 4, wherein thebase is sodium methoxide or sodium hydride.
 8. The process for preparingan alkali metal salt of a β-oxonitrile compound according to any one ofclaims 1 to 4, wherein the base is sodium methoxide.
 9. The process forpreparing an alkali metal salt of a β-oxonitrile compound according toany one of claims 1 to 8, wherein the base is used in an amount of 0.05to 10 mol based on 1 mol of the carboxylic ester.
 10. The process forpreparing an alkali metal salt of a β-oxonitrile compound according toany one of claims 1 to 8, wherein the base is used in an amount of 0.1to 5 mol based on 1 mol of the carboxylic ester.
 11. The process forpreparing an alkali metal salt of a β-oxonitrile compound according toany one of claims 1 to 10, wherein the reaction is carried out in thepresence or absence of a solvent.
 12. The process for preparing analkali metal salt of a β-oxonitrile compound according to any one ofclaims 1 to 10, wherein the reaction is carried out in the presence of asolvent selected from the group consisting of a cyclic aliphatichydrocarbon, a halogenated aliphatic hydrocarbon, an aromatichydrocarbon, a halogenated aromatic hydrocarbon, a nitrated aromatichydrocarbon and an alcohol.
 13. The process for preparing an alkalimetal salt of a β-oxonitrile compound according to any one of claims 1to 10, wherein the reaction is carried out in the presence of a solventselected from the group consisting of cyclohexane, cycloheptane,cyclooctane, 1,2-dichloroethane, toluene, xylene, cumene, chlorobenzene,bromobenzene, nitrobenzene, methanol, ethanol, n-propyl alcohol,isopropyl alcohol, n-butyl alcohol, isobutyl alcohol and t-butylalcohol.
 14. The process for preparing an alkali metal salt of aβ-oxonitrile compound according to any one of claims 1 to 13, whereinthe solvent is used in an amount of 0 to 100 ml based on 1 g of thecarboxylic ester.
 15. The process for preparing an alkali metal salt ofa β-oxonitrile compound according to any one of claims 1 to 13, whereinthe solvent is used in an amount of 0 to 20 ml based on 1 g of thecarboxylic ester.
 16. A process for preparing a β-oxonitrile compoundwhich comprises neutralizing an alkali metal salt of the β-oxonitrilecompound obtainable by the process as defined in any one of claims 1 to15 with an acid.
 17. The process for preparing a β-oxonitrile compoundaccording to claim 16, wherein the acid is selected from the groupconsisting of hydrochloric acid, nitric acid and sulfuric acid.